Home as the new frontier for the treatment of COVID-19: the case for anti-inflammatory agents

Abstract

COVID-19, caused by SARS-CoV-2, is characterised by a broad spectrum of symptom severity that requires varying amounts of care according to the different stages of the disease. Intervening at the onset of mild to moderate COVID-19 symptoms in the outpatient setting would provide the opportunity to prevent progression to a more severe illness and long-term complications. As early disease symptoms variably reflect an underlying excessive inflammatory response to the viral infection, the use of anti-inflammatory drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), in the initial outpatient stage of COVID-19 seems to be a valuable therapeutic strategy. A few observational studies have tested NSAIDs (especially relatively selective COX-2 inhibitors), often as part of multipharmacological protocols, for early outpatient treatment of COVID-19. The findings from these studies are promising and point to a crucial role of NSAIDs for the at-home management of people with initial COVID-19 symptoms.

Figure 1

Proposed maladaptive hyperinflammatory response to SARS-CoV-2 infection SARS-CoV-2 enters target host cells by interacting through its spike subunit with ACE2, after being primed by TMPRSS2. The virus induces cell damage through direct cytotoxic effects and after newly formed virions are released by exocytosis into the extracellular compartment. In addition, a dysregulated immune response eventually leads to the recruitment and activation of macrophages and neutrophils, with the release of cytokines, chemokines, and other inflammatory mediators determining hyperinflammation. At the same time, activation of the complement system and excessive cytokine production activate endothelial cells and disrupt vascular integrity leading to microthrombi deposition and microvascular dysfunction.

Figure 2

Prostanoid production and NSAIDs The 20-carbon fatty acid arachidonic acid is released from membrane phospholipids by phospholipase A₂, which is activated by physical, chemical, and inflammatory stimuli. Arachidonic acid is converted by COX-1 and COX-2 to the unstable intermediate PGH₂. By tissue-specific isomerases, PGH₂ is metabolised to bioactive prostanoids, which include PGE₂, PGD₂, PGF_2α, TxA₂, and PGI₂. After binding to their receptors (EPr_1–4, DPr₁, DPr₂, FP_α, FP_β, TP_α, TP_β, and IP), prostanoids elicit a wide variety of biological effects involved in homoeostatic and normal tissue function but also implicated in pathophysiological processes including infection, thrombosis, and inflammation. The principal therapeutic effect of NSAIDs is related to their capability to inhibit the cyclooxygenase activity of COX-1 and COX-2 enzymes, eventually suppressing the formation of prostanoids. DC=dendritic cell. NSAIDs=non-steroidal anti-inflammatory drugs.

Figure 3

Options for at-home anti-inflammatory therapy in adults with COVID-19 depending on disease stage MEWS=Modified Early Warning Score (an international, universal scoring scale from multiple parameters including respiratory rate, SpO₂, heart rate, systolic blood pressure, consciousness). NSAIDs=non-steroidal anti-inflammatory drugs. SpO₂=oxygen saturation.